Biologics are becoming the mainstay of moderate-to-severe psoriasis treatment as they are effective, cause minor organ damage, and require fewer hospital visits than existing therapies. Currently, six drugs are used to treat psoriasis: IFX, adalimumab (ADA), ustekinumab (UST), SEC, ixekizumab (IXE), and brodalumab (BRO). The main types of psoriasis are psoriatic arthritis (PsA), GPP, and erythrodermic psoriasis (EP). In Japan, the treatment options for PV and PsA are IFX, ADA, UST, and SEC; treatment options for GPP are IFX and SEC; and treatment options for EP are IFX and SEC only. Cyclosporine (CyA) has a long history of use in dermatology, and its efficacy, dosage, and methods for managing its side effects are well established. However, since biologics are now available, concerns on the side effects of long-term administration of CyA, such as increased blood pressure and renal damage, exist. Several case reports evaluated the combination of GMA and CyA for GPP. However, there are very few English reports on the effectiveness of the combination of biologics and GMA for GPP. Fujisawa et al. reported the efficacy of IFX + GMA combination therapy in patients with GPP who failed to respond to IFX [3]. This is the first case study that reports on the combined administration of SEC and GMA both instituted since admission for severe GPP, with immediate patient response to treatment. Furthermore, when considering the pathogenesis of GPP, the suppression of IL-17A and removal of activated neutrophils are expected to be highly effective.
According to the 2003–2006 data retrieved from the Japanese Psoriasis Association, pustular psoriasis accounts for approximately 1% of all psoriasis cases, with the majority of patients being children and adults in their 30 s [2]. Men are twice as likely as women to be affected by PV, while pustular psoriasis is slightly more common in women (1.2 times more common than in men). The skin-related symptoms (erythema, pustules, edema) and findings associated with systemic inflammation (fever, white blood cell count, CRP level, and albumin level) were scored, and the total score was used to classify the disease as mild, moderate, or severe (Additional file 1: Figure S1). For the treatment of GPP, etretinate, cyclosporine, methotrexate, and corticosteroids are the drugs of choice, and topical medications, phototherapy, and GMA have been attempted. GPP is a disease that usually presents with fever, generalized flushing, and multiple aseptic pustules on the skin, which histopathologically appear as subcorneal leisons characterized by Kogoj spongiform pustules. PV may or may not be preceded by a psoriatic eruption, but recurrent episodes characterize it. Although it is a life-threatening disease caused by a systemic inflammatory reaction, it is difficult to treat because treatment options are limited, and indications may be limited by the patient's background comorbidities, such as cancer or active inflammatory disease. In this case, the patient had a markedly elevated inflammatory response with a white blood cell count of 16,610/μL and a C-reactive protein (CRP) of 31.8 mg/dL. In addition, urinary L-FABP was also elevated at 57.5 μg/gCre for AKI with sCre 2.43 mg/dL, which was expected to increase prognostic risk [4]. As shown below, the patient was also severely ill, with a severity score of 15 points. Therefore, we judged that prompt therapeutic intervention was necessary.
The pathogenesis of psoriasis involves various factors in the genetic landscape, and a strong correlation with HLA-Cw6 has been reported [5]. Various dendritic cells, lymphocytes, and cytokines are intricately involved in the histology of psoriatic lesions, and TNF-α, IL-23, and IL-17 are thought to play crucial roles [6]. Psoriasis is a chronic inflammatory skin disease, and several new drugs targeting the IL-23/IL-17A pathway have recently been approved and are undergoing clinical development. In the mid-2000s, IL-23 was observed to induce the production of IL-17 by activated T lymphocytes (later named Th17 cells) [7, 8]. The involvement of IL-23 in psoriasis is supported by its ability to induce psoriasis-like characteristics in a preclinical model following intradermal administration [9]. This phenotype is associated with the infiltration of IL-22-and IL-17A-producing T cells [10]. Therefore, Th17 cells have been extensively studied, and IL-17A, a characteristic cytokine expressed on neutrophils, has been identified as an important causative factor of psoriasis [6, 11].
SEC is a fully human monoclonal IgG1 antibody that targets IL-17A. SEC is characterized by (1) several indications, (2) the rapid onset of therapeutic effects, (3) long-lasting therapeutic effects, (4) low economic burden, (5) easy dose reduction, and (6) low risk of interstitial pneumonia. SEC is the first-line treatment for PV and PsA due to its excellent efficacy, safety, and economic efficiency. Furthermore, it can also be used in elderly patients with psoriasis as dose reduction is easy. The initial dose is 300 mg, followed by five subcutaneous doses at 1, 2, 3, and 4 weeks and every four weeks thereafter. For patients weighing ≤ 60 kg, 150 mg doses should be considered. In clinical trials conducted overseas, the therapeutic effect of 300 mg SEC on psoriatic rashes was 81.6% for the Psoriasis Area and Severity Index (PASI) 75 remission and 59.2% for the PASI 90 remission at week 12 [12]. In a Japanese clinical trial for psoriasis, PASI 75 and PASI 90 were achieved in 82.8% and 92.1% of the patients, respectively, at week 12 [13].
GMA is an extracorporeal therapy that eradicates neutrophils, macrophages, and monocytes that accumulate in inflammatory tissues, contribute to lesion formation and regulate cellular functions. Granulocytes and monocytes are adsorbed onto the Adacolumn carrier via the IgG-FcγR and iC3b-CR3 (Mac-1) ligand-receptor interactions as granulocytes and monocytes recognize the page as a foreign entity and capture it [14]. Passage cells are contact-stimulated and return to the organisms with modified functions. Moreover, superficial and deep veins may be used for access as the blood flow in the treatment is low. Safer puncture under echo guidance in GMA has also been applied previously [15]. In the present case, a blood access catheter was inserted as the patient had severe skin symptoms in the elbow fossa and few signs around the neck. Multicenter trials have been conducted to confirm the efficacy and safety of GMA [16], but no randomized controlled trials have been conducted. Due to the limited number of patients, the large number of severe cases, and nature of extracorporeal circulation therapy, it is difficult to conduct a double-blind, placebo-controlled study; therefore, the accumulation of case reports is expected. A previous report described a mechanism of selective adsorption and removal of activated pathological granulocytes and monocytes [17], which is expected to be beneficial based on the response mechanism. Many IL-17 products, including SEC, are administered weekly for the first month in order to reach the therapeutic plasma concentrations, so as to allow them to work immediately; however, it takes the drug an average of 6 days [18] to reach peak serum concentrations, thus it is unlikely that its full efficacy is realized within the first 2–3 days of treatment [19]. During an acute exacerbation of GPP, there is often no time window of a week because of the rapid progression of systemic inflammation due to cytokine storm. Our patient’s case was a particularly severe one, with underlying conditions such as poorly controlled DM and AKI on CKD, and the rapid systemic fluid overload could threaten the circulatory system. Because SEC alone would leave the patient exposed to a life-threatening condition before it was fully effective, GMA was used in combination with SEC in this case. Due to its mechanical properties, GMA should be promptly effective immediately after administration and is expected to confer an immediate therapeutic benefit. In the present case, GMA was remarkably effective immediately after treatment. GMA is also easy to introduce because many of its side effects are minor and are not limited by patient background conditions, such as comorbidities or age. Recently, Yoshikawa et al. reported a case of impetigo herpetiformis, a pregnancy-associated variant of GPP that was refractory to treatment despite various therapies and GMA, in which remission was induced after the introduction of SEC [20].
In conclusion, GMA can eliminate activated leukocytes, and the early introduction of IL-17 monoclonal antibody combined with GMA may allow disease suppression in patients with severe GPP, thus avoiding the progression to multiorgan failure. Further studies may verify the effects of IL-17 monoclonal antibodies and GMA on severe GPP.